PROJECT ABSTRACT Colorectal cancer (CRC) is one of the leading causes of death in most developed countries including the United States. The major cause of CRC patient death is by hepatic metastasis. Despite intensive studies, our knowledge about the nature of CRC metastasis cues and the mechanisms underlying their origination is still limited. Standard chemotherapy for CRC tumors relies on a number of cytotoxic drugs, targeted agents and their combinations. However, to date, we have no specific therapy for metastatic colorectal cancer. There is an increasing need to develop alternative drugs targeting specific pathways that inhibit colorectal tumor growth and hepatic metastasis. The objective of this investigation is to develop salinomycin and MST-312 as novel therapeutic strategies for metastatic colorectal cancer. Salinomycin is a polyether antibiotic isolated from Streptomyces albus that acts as a potassium ionophore. Salinomycin possesses selective cancer stem cell inhibitory activity. We herein combine salinomycin with MST-312 for synergistic effects against metastasis. MST-312 (telomerase inhibitor IX) is a synthetic compound that acts as a telomerase inhibitor. Our central hypothesis is that dual targeting cancer stem cell and telomerase may synergize their anti-tumor effects and block hepatic metastasis via the eradication of colorectal cancer stem cells. We will test this hypothesis by performing the following specific aims. Aim 1: To determine whether hTERT signaling axis promotes the tumor initiation, drug resistance and metastatic potential of CD51+ colorectal cancer cells. Aim 2: To demonstrate that dual targeting CSCs and telomerase in colorectal cancer cells with salinomycin and MST- 312 significantly reduces cell invasiveness and stem cell-like traits compared to targeting CSCs and telomerase alone. Aim 3: To demonstrate in animal models that dual targeting with salinomycin and MST-312 inhibits the colon tumor proliferation and hepatic metastasis from colorectal cancer xenografts compared to either agent alone. The results from the proposed experiments would expand our understanding of mechanisms of colon CSCs growth and metastasis inhibition resulting in a paradigm shift in treatment of CRC improving outcome for this deadly disease.